Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension :

Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.

Circulation Research, 86(5), 494-501

Chronic renal failure (CRF) is associated with oxidative stress, the mechanism of which remains uncertain. Superoxide is the primary oxygen free radical produced in the body, NAD(P)H oxidase is the major source of superoxide production and superoxide dismutase (SOD) is responsible for removal of superoxide. We hypothesized that CRF-induced oxidative stress may be due to increased production and/or decreased dismutation of superoxide. Immunodetectable superoxide dismutase isoforms (Cu Zn SOD and Mn SOD), as well as, NAD(P)H oxidase (gp91 phox subunit) proteins and xanthine oxidase (XO) activity were determined in the kidney and liver of CRF (5/6 nephrectomized) and sham-operated control rats. Subgroups of animals were treated with SOD-mimetic drug, tempol and blood pressure and urinary nitric oxide metabolites (NOx) were monitored. The CRF group showed marked down-regulations of CuZn SOD and Mn SOD and significant up-regulation of gp91 phox in the liver and kidney, which are among the metabolically most active tissues. In contrast, XO activity was depressed in both tissues. Arterial pressure and nitrotyrosine abundance were elevated while urinary NOx excretion was depressed, pointing to increased NO inactivation by superoxide and decreased NO availability in CRF animals. Administration of SOD-mimetic agent, tempol, for one week, ameliorated hypertension, reduced nitrotyrosine abundance and increased urinary NOx excretion in the CRF animals. CRF is associated with depressed SOD and elevated NAD(P)H oxidase expression, which can contribute to oxidative stress by increasing superoxide. This is evidenced by favorable response to administration of SOD-mimetic drug, tempol, and increased nitrotyrosine that is the footprint of NO interaction with superoxide.